1-(4{40 -hydroxy-3{40 -(hydroxy methyl)-phenyl)-1-hydroxy-2-aralkylaminoethanes

ABSTRACT

The 1-(4&#39;&#39;-hydroxy-3&#39;&#39;-(hydroxymethyl)-phenyl)-1-hydroxy-2aralkylaminoethanes are useful as bronchodilating agents. The compound Alpha 1-((( Alpha -methyl-3,4-methylenedioxyphenethyl)amino)-methyl)-4-hydroxy-m-xylene- Alpha 1, Alpha 3-diol is especially useful since it is an excellent bronchodilator and yet exerts only a minimal effect on cardiac muscle.

United States Patent Suh et al. 1 Oct. 24, 1972 [54] 1-(4-HYDROXY-3'-(HYDROXY [56] References Cited METHYL)-PHENYL)-l-HYDROXY-2- TATE ARALKYLAMINOETHANES 3 502 679 S$2 H rShPATENTS [72] Inventors: John T. Suh, Mequon; Thomas M. om an at "260/3405 x Bare, Milwaukee, both of WIS. Primary Examiner Alex Maze] [73] Assignee: Colgate-Palmolive Company, New Assistant Examiner-James H. Tumipseed York, NY. Att0rneyT. F. Kryshak and M. L. Youngs 22 Filed: June 4, 1971 [57] ABSTRACT [21] Appl- N04 150,220 The l-[4'-hydroxy-3'-(hydroxymethyl)-phenyl]-lhydroxy-2-aralkylaminoethanes are useful as 52 vs. C] ..260/340.5, 424/282 bronehedilefing agents The compound [51] Int.Cl. ..C07d 13/10 y A- y yp y l- 58 Field of Search ..260/340.5 y 1- y yy is especially useful since it is an excellent bronchodilator and yet exerts only a minimal effect on cardiac muscle.

6 Claims, No Drawings 1 1-(4'-HYDROXY-3 -(HYDROXY METHYL)- PHENYL)-l-HYDROXY-2- ARALKYLAMINOETHANES BACKGROUND OF THE INVENTION The most widely used bronchodilators, such as isoproterenol, are not orally effective and have the disadvantage of being potent cardiac muscle stimulents. The compound a-(3,4-dihydroxyphenyl)-B-(3, 4-

methylenedioxyphenyl)-isopropylamino ethanol, disl closed in US. Pat. No. 3,139,441, is orally effective as a bronchodilator but is a potent cardiac stimulant. I-Iydroxymethylated sympathomimetic amines have been disclosed which are bronchodilators and cardiac stimulants. D. Hartley, et al., Nature, 219, 861 (1968), and D. T. Collin, et al., J. Med. Chem, 13, 674 1970).

DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention have the following formula:

with hydrochloric acid to form the compound 2- benzyloxy-S-(a-methyl-3,4-methylenedi0xyphenethylaminoacetyl)-benzyl acetate hydrochloride. The benzylacetate is then hydrolyzed in the presence of a dilute acid such as dilute hydrochloric acid to form 2- benzyloxy--(a-methyl-3,4-methylenedioxyphenethylaminoacetyl)-benzyl alcohol, which is hydrogenated to form a-[ [(a-methyl-3 ,4-methylenedioxyphenethyl)amino]methyl]-4-hydroxy-m-xylene-a,a diol.

The hydrogenation is preferably conducted in the presence of a platinum or palladium catalyst at hydrogen pressure of 40-60 p.s.i. and a temperature of from room temperature to about 50C. The reaction is considered complete when the hydrogen uptake has leveled off or ceased.

The described method of preparation may be illustrated as follows 0 CH3 0 Ph I 1) NH 3 ()Ac 0 0 NH-HCl c/ (I) HCLHzO H3 2 NaOH I OH Q OH G I A I OH NH NH O O f Hz, Pd/C CH2 I CH2 isomers having different melting points. The high melting isomer may be isolated from the low melting isomer in a substantially pure form by forming the nitrate salts of the two isomers and selectively precipitating the nitrate salts from a solvent such as anhydrous ether. The high melting isomer precipitates first and can be purified, if desired, by recrystallization from a suitable solvent such as 2-propanol. The purified high melting isomer is a white solid which has a melting point of about 127135 c.

Both of the diastereoisomers, as well as the mixture of the isomers of a -[[(a-methyl-S,4-methylenedioxyphenethyl)amino]methyl]-4-hydroxy-m-xylene-a,a ,-diol, are orally effective as bronchodilators and produce a more potent and sustained bronchodilation than isoproterenol. Furthermore, both isomers have less undesirable side effects on the contractile forces and heart rate of test animals than does isoproterenol.

Pharmaceutical compositions will generally contain the novel compounds as a mixture of diastereoisomers or optical isomers if more than one form exists. Such compositions may take the form of tablets, capsules, solutions or suspensions for oral administration or solutions for inhalation or parenteral administration. The active ingredients are generally employed in the form of their free bases. However, they may be employed in the form of their acid addition salts such as the nitrates, the hydrochlorides, the sulfates and the like. In addition to the active ingredients, the compositions will usually contain conventional pharmaceutical diluents and excipients.

The individual dosage forms may contain from about 0.02 mg. or less of the active ingredient calculated as the free base to more than mg. Generally, the daily dose will be equivalent in terms of the free base to an intraperitoneal dose of from about 2 mg/kg to about 200 mg/kg of body weight.

The invention is further illustrated by the examples which follow.

EXAMPLE 1 3-Chloromethyl-4-hydroxyacetophenone EXAMPLE 2 5-Acety1-2-hydroxybenzylacetate A stirred mixture of 40.0 g. (216 moles) of the com- I pound of Example 1 and 25.8 g. (263 moles) of potassium acetate in 90 ml. of glacial acetic acid is heated for 3 hours at lQ0.,.The,resulting mixture is poured into water and extracted with methylene chloride. The com bined organiciextracts are washed with water, diluted withbenzene, dried over MgSO filtered, and concentrated to leave a tan solid which is recrystallized from ethyl acetate to leave 5-acetyl-2-hydroxybenzylacetate as tan crystals, m.p. l11-112.

EXAMPLE 3 S-Acetyl -2-hydroxybenzylalchol A solution of 41.6 g. (0.20 mole) of the benzyl acetate of Example 2 and 0.15 g. of p-toluenesulfonic acid in 230 ml. of methanol is heated to reflux and the methyl acetate-methyl alcohol distillate was slowly removed through a Vigreux column using a high reflux ratio. When ml. of distillate has been collected (6.5 hours), the reaction mixture is concentrated, poured into water, and extracted with ether. The combined ether extracts are washed successively with water, dilute aqueous sodium carbonate, and water, dried over MgSO filtered, and concentrated to leave a brown oil. A small volume of ethyl acetate is added and the resulting mixture placed in the refrigerator overnight. The resulting crystals are collected and dried to give 5-acetyl-2-hydroxybenzylalcohol as a tan solid, mp. 120.5-121.5.

EXAMPLE 4 5Acetyl-2-benzyloxybenzylalcohol To a cold stirred solution of 5-acetyl-2-hydroxybenzyl-alcohol (14.56 g. or 87.8 mmoles) in 140 ml. of acetone is added a solution of 6.71 g. (93.5 mmoles) of percent potassium hydroxide in 8.2 ml. of water. The potassium salt separates as a yellow precipitate and after standing in the cold for 1 hour, is collected and air-dried. The potassium salt is then refluxed under nitrogen with 15.0 g. (87.8 mmoles) of benzyl bromide and ml. of absolute ethanol for 6 hours. The separated potassium bromide is separated by filtration and the filtrate concentrated to a total volume of ca. 60 m1. On cooling, tan crystals separate and these are collected, washed with cold ethanol-n-heptane, and dried to give 5-acetyl-2-benzyloxybenzylalcohol as pale tan needles, mp. 124125. An additional amount of tan needles, mp. 122.5-124, are isolated from the mother liquor by concentration and recrystallization of the residue from ethanol.

EXAMPLE 5 5-Acetyl-2-benzyloxybenzyl acetate A solution of 28.80 g. (112 mmoles) of 5-acetyl-2- benzyloxybenzyl alcohol in 65 ml. of pyridine and 32 m1. of acetic anhydride is heated at 100 for 0.5 hour. The resulting solution is cooled, poured into 300 m1. of water and diluted with solid sodium bicarbonate until gas evolution ceases. The resulting mixture is extracted with ether and the combined ether extracts are washed successively with dilute hydrochloric acid (until the washes are acidic), water, and dilute sodium bicarbonate. The ether layer is dried over MgSO filtered, and concentrated to leave a pale orange oil which slowly crystallizes. The solid is recrystallized from a small amount of ethanol to give 5-acetyl-2- benzyloxybenzyl acetate as pale tan crystals, m.p. 51.552.5.

EXAMPLE 6 2-Benzyloxy-5-bromoacetylbenzy1 acetate To a stirred solution of 5-acetyl-2-benzyloxybenzy1 acetate (31.10 g. or 104 mmoles) in 500 ml. of anhydrous ether is added ca. 0.05 g. of aluminum chloride and 16.7 g. (104 mmoles) of bromine (dropwise). The resulting mixture is filtered through Celite and concentrated to leave a white solid which is dissolved in an ether-methylene chloride mixture. The organic material is washed with dilute aqueous sodium bicarbonate, dried over MgSO filtered, and concentrated to leave a white solid which is recrystallized from a small volume of ethanol to give 2-benzyloxy-5-bromoacetylbenzyl acetate as white needles, m.p. 89-90.

EXAMPLE 7 2-Benzyloxy-5-[(oz-methyl- 3 ,4methylenedioxyphenethyl )aminoacetyl]-benzyl acetate hydrochloride To a cold stirred solution of 6.99 g. (0.39 mmoles) of a-methyl-3,4-methylenedioxyphenethylamine in 13 ml. of tetrahydrofuran (Tl-IF) is added dropwise a solution of 7.00 g. (18.6 mmoles) of the bromoketone in 28 ml. of THF. The solution is heated to 4045 for 1.5 hours, whereupon a white precipitate forms. The mixture is cooled and filtered to separate 4.12 g. (85.5 per cent) of a-methyl-3,4-methylenedioxyphenethylamine hydrobromide. The filtrate is concentrated to give a brown oil which is dissolved in ml. of ethanol and acidified with ethereal hydrochloric acid. The resulting precipitate is collected, washed with ethanol-ether, and dried to give 2-benzyloxy-5-[(a-methyl-3,4- mcthylenedioxyphenethyl)aminoacetyl]-benzyl acetate hydrochloride as a tan solid, mp. 140-l41.

EXAMPLE 8 2-Benzyloxy-5 (a-methyl-3 ,4- methylenedioxyphenethyl )aminoacetyl -benzyl alcohol A stirred mixture of 4.20 g. (8.21 mmoles) of the benzyl acetate of Example 7, 50 ml. of dilute hydrochloric acid (5 ml. concentrated HCl 45 ml. water), and 30 ml. of methanol is heated at 80-85 for 1 hours. The solution is cooled, made basic with aqueous sodium hydroxide, and diluted with 30 ml. of ether. Vigorous stirring eventually solidifies the precipitated oil and, on filtration, a tan solid is collected. Recrystallization of the solid from methanol gives 2-benzyloxy-5- [(a-methyl-3,4-methylenedioxyphenethyl) aminoacetyl]-benzyl alcohol as atan solid, mp. 83.

EXAMPLE 9 a-[ a-Methy1-3 ,4-methylenedioxyphenethyl )amino] methyl]-4-hydroxy-m-xylene-oz ,a -diol A mixture of 5.65 g. (13.0 mmoles) of the aminoketone of Example 8, 0.60 g. of 10 percent Pd/C, and 60 ml. of methanol is hydrogenated on the Parr shaker for 13 hours. The resulting mixture is filtered and concentrated to leave a white foam which, upon dissolving in 15 ml. of ethyl acetate and scratching with a glass'rod, deposits a white solid, mp. 90. Recrystallization by dissolving in a small amount of acetone and diluting with ethyl acetate gives a-[[(a-methyl-3,4- methylenedjoxyphenethyl)amino]methyl]-4-hydroxym-xylene-a ,a -diol as a white solid, mp. 91.

Anal. Calcd. for C H NO z C, 66.07; H, 6.71; N,

Found: C, 66.17; H, 6.62; N, 3.99.

EXAMPLE 10 a [(a-Methyl-3 ,4-methylenedioxyphenethyl )amino] methyl]-4-hydroxy-m-xylene-a,a -diol nitrate A stirred solution of 5.6 g. (0.0163 mole) of a-[[(amethyl-3,4-methylenedioxyphenethyl)amino]methyl]- 4-hydroxy-m-xylene-a,a -diol in 37 ml. of tetrahydrofuran is cooled in an ice bath, and a solution of 8.4 ml. of 20% HNO in tetrahydrofuran is added dropwise in 5 minutes. The solution is then tested to assure an acidic pH, after which it is diluted to ml. with ether. The oily precipitate is scratched to initiate crystallization, after which the mixture is cooled. The solid is then collected, washed with ether and air-dried to yield a while solid, mp. 9298.

The above solid is recrystallized several times from minimal amounts of 2-propanol. Several additional purifications are carried out where successively higher melting solid and subsequent crops are combined and recrystallized to yield a solid product which is then recrystallized several times from ethanol to eventually yield a-[ [(a-methyl-3 ,4-methylenedioxyphenethyl)amino]methyl]-4-hydroxy-m-xylene-a ,a diol nitrate in the form of a white solid, mp. 136.5-1 40.

Anal. Calcd. for C H N O 6.86. Found: C, 55.67; H, 6.01; N, 6.62.

The mother liquors from the above recrystallizations are combined and concentrated. Additional amounts of the above-described high melting isomer are removed by recrystallizing it from 2-propanol. The product which ultimately dissolves in a minimum amount of 2- propanol is purified further by warming in small amounts of dioxane, removing the insoluble material and then recrystallizing the soluble product from dioxane to give the low melting isomer, m.p. 108.51 10. Anal. Calcd. for C, 1-1 N O C, 55.87; H, 5.92; N,

C, 55.87; H, 5.92; N,

6.86. Found: C, 55.67; H, 6.29; N, 6.14.

EXAMPLE 11 2-Benzyloxy-5-[ 3 ,4-methylenedioxyphenethyl) aminoacetyl]-benzyl acetate hydrochloride To a cold stirred solution of 4.61 g. (27.9 mmoles) of 3,4-methylenedioxyphenethylamine in 9.6 ml. of THF is added dropwise a solution of 5.00 g. (13.3 mmoles) of 2-benzyloxy-5-bromoacetylbenzyl acetate in 20 m1. of THF. A precipitate forms during the addition, and after the addition is complete, the mixture is stirred at room temperature for 45 minutes, cooled, diluted with 10 ml. of ether, and filtered to separate 3.17 g. (96.5 percent) of 3,4-methylenedioxyphenethylamine hydrobromide. The filtrate is concentrated and the residue dissolved in 10 m1. of methanol. Acidification of this solution with ethereal l-lCl and dilution of the resulting solution with a small amount of ether precipitates a white solid which is collected and dried to give 2-benzyloxy-5-[ 3 ,4-methylenedioxyphenethyl) aminoacetyllbenzyl acetate hydrochloride as a white solid, m.p. 186-187.

EXAMPLE l2 2-Benzyloxy--[ (3 ,4- methylenedioxyphenethyl)aminoacetylbenzyl alcohol EXAMPLE 13 a-[ [(3 ,4-methylenedioxyphenethyl )amino1methyl ]-4- hydroxy-m-xylene-a,a -diol A mixture of 6.32 g. (15.01 mmoles) of the aminoketone of Example 12, 0.63 g. of 10% Pd/C, and 85 ml. of methanol is hydrogenated using the Parr apparatus for a total of 17.75 hours with fresh catalyst added at the end of 7.75 hours and 12.75 hours. The resulting mixture is filtered through Celite and the filtrate concentrated to leave an orange foam which is induced to crystallize by scratching with a glass rod in the presence of ethyl acetate. A light orange solid, m.p. l17119, is collected and recrystallized from methanol-ethyl acetate to give a -[[(3,4-methylenedioxyphenethyl)amino]methyll-4-hydroxy-m-xylene-a ,a -diol as pale tan crystals, m.p. 123.5124.5. An additional recrystallization from methanol-ethyl acetate yields a-[ 3 ,4-methylenedioxyphenethyl)amino]methyl]-4-hydroxy-m-xylene-a.01"- diol as white crystals, m.p. l24l25.

Anal. Calcd. for C l-l N C, 65.24; H, 6.39; N, 4.23. Found: C, 65.58; H, 6.34; N, 4.12.

EXAMPLE 14 2-Benzyloxy-5-[(apt-dimethyl-3,4-methylenedioxyphenethyl)aminoacetyl]benzyl acetate hydrochloride To a stirred solution of l 1.8 g. (61.3 mmoles) of 01,0:- dimethyl-3,4-methylenedioxyphenethylamine in 21 ml. of THF (tetrahydrofuran) is added dropwise a solution of 11.0 g. (29.2 mmoles) of 2-benzyloxy-5- bromoacetyl benzyl acetate in 44 ml. of THF. During the addition, the temperature of the reaction mixture is maintained at 25-30; after the addition is completed,

the solution is warmed at 35 for 1.5 hours. After one separate 8.00 g. (100%) of a,a-dimethyl-3,4- methylene-dioxyphenethylamine hydrobromide. The filtrate is concentrated to leave a pale yellow gum which is dissolved in an ethanol-methanol mixture and acidified with ethereal hydrochloric acid. The resulting precipitate is collected, washed with cold isopropanol, and dried to give pale yellow crystals, m.p. 214. Recrystallization from methanol gives 2-benzyloxy-5-[ (a,a-dimethyl-3,4-methylenedioxyphenethyl) aminoacetyflbenzyl acetate hydrochloride as white crystals, m.p. 215.

EXAMPLE 15 2-Benzyloxy-5-[(0:,0z-dimethyl-3,4-methylenel.l..q 9 hsnsth in t b nz al A mixture of 7.12 g. (13.5 nmoles) of the benzyl methanol, and 6.5 ml. 6fconcentratedhytlrdchloric acid is heated at -85 for 1 hour and then cooled. The oil which initially separates soon solidifies and the resulting suspension is made basic by adding 20 percent aqueous sodium hydroxide. The resulting solid is collected, washed thoroughly with water and air-dried. Recrystallization from methanol gives 2-benzyloxy-5-[ (a,a-dimethyl-3,4-methylenedioxyphenethyl)aminoacetyl1benzyl alcohol as small white crystals, m.p. 228.

EXAMPLE 16 a [(a,a-Dimethyl-3 ,4-methylenedioxyphenethyl) amino]methyl]4-hydroxy-m-xylene-a,a -diol A mixture of 3.50 g. (7.82 mmoles) of the aminoketone of Example 15, 0.35 g. of 10 percent palladium-on-carbon, and 38 ml. of methanol is hydrogenated (50 psi) using the Parr apparatus. After 7.5 hours, the mixture is filtered and concentrated to leave a gum which is dissolved in hot isopropanol; on cooling the resulting solution, white crystals form and are collected and dried to give a-[[(a,60 -dimethyl- 3,4-methylenedioxyphenethyl)amino]methyl]-4- hydroxy-m-xylene-a,a -diol, m.p. 106.

We claim:

1. A compound selected from the group consisting of a compound of the formula in which R and R are hydrogen or lower alkyl and pharmaceutically acceptable salts thereof.

2. A compound of claim 1 in which R and R are methyl.

3. A compound of claim 1 in which R and R are hydrogen.

4. A compound of claim in which R is hydrogen and R is methyl.

5. A diastereoisomer of the compound of claim 1 in which R is hydrogen and R is methyl, which isomer has a melting point of l27135 C.

6. A diastereoisomer of the compound of claim 1 in which R is hydrogen and R is methyl, which isomer has a melting point of 73-77 C. 

2. A compound of claim 1 in which R and R1 are methyl.
 3. A compound of claim 1 in which R and R1 are hydrogen.
 4. A compound of claim 1 in which R is hydrogen and R1 is methyl.
 5. A diastereoisomer of the compound of claim 1 in which R is hydrogen and R1 is methyl, which isomer has a melting Point of 127* - 135* C.
 6. A diastereoisomer of the compound of claim 1 in which R is hydrogen and R1 is methyl, which isomer has a melting point of 73* - 77* C. 